Trans-radial approach versus trans-femoral approach in patients with acute coronary syndrome undergoing percutaneous coronary intervention: An updated meta-analysis of randomized controlled trials

Introduction Trans-radial approach (TRA) is recommended over trans-femoral approach (TFA) in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). We intended to study the effect of access on all-cause mortality. Methods and results We searched PubMed and EMBASE for randomized studies on patients with ACS undergoing PCI. The primary outcome was all-cause mortality at 30-days. The secondary outcomes included in-hospital mortality, major adverse cardiac or cerebrovascular event (MACE) as defined by the study, net adverse clinical event (NACE), non-fatal myocardial infarction, non-fatal stroke, stent thrombosis, study-defined major bleeding, and minor bleeding, vascular complications, hematoma, pseudoaneurysm, non-access site bleeding, need for transfusion, access site cross-over, contrast volume, procedure duration, and hospital stay duration. We studied 20,122 ACS patients, including 10,037 and 10,085 patients undergoing trans-radial and trans-femoral approaches, respectively. We found mortality benefit in patients with ACS for the trans-radial approach [(1.7% vs. 2.3%; RR: 0.75; 95% CI: 0.62–0.91; P = 0.004; I2 = 0%). Out of 10,465 patients with STEMI, 5,189 patients had TRA and 5,276 had TFA procedures. A similar benefit was observed in patients with STEMI alone [(2.3% vs. 3.3%; RR: 0.71; 95% CI: 0.56–0.90; P = 0.004; I2 = 0%). We observed reduced MACE, NACE, major bleeding, vascular complications, and pseudoaneurysms. No difference in re-infarction, stroke, and serious bleeding requiring blood transfusions were noted. We noticed a small decrease in contrast volume(ml) {mean difference (95% CI): −4.6 [−8.5 to −0.7]}, small but significantly increase in procedural time {mean difference (95% CI) 1.2 [0.1 to 2.3]}and fluoroscopy time {mean difference (95% CI) 0.8 [0.3 to1.4] min} in the trans-radial group. Conclusion TRA has significantly reduced 30-day all-cause mortality among patients undergoing PCI for ACS. TRA should be the preferred vascular access in patients with ACS.


Introduction
Trans-radial approach (TRA) is recommended over trans-femoral approach (TFA) in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). We intended to study the effect of access on all-cause mortality.

Methods and results
We searched PubMed and EMBASE for randomized studies on patients with ACS undergoing PCI. The primary outcome was all-cause mortality at 30-days. The secondary outcomes included in-hospital mortality, major adverse cardiac or cerebrovascular event (MACE) as defined by the study, net adverse clinical event (NACE), non-fatal myocardial infarction, non-fatal stroke, stent thrombosis, study-defined major bleeding, and minor bleeding, vascular complications, hematoma, pseudoaneurysm, non-access site bleeding, need for a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 Introduction Cardiovascular diseases are one of the leading causes of morbidity and mortality affecting millions of people worldwide [1]. Management of acute coronary syndrome (ACS) has evolved over a period of time to reach its current position. Percutaneous coronary intervention (PCI) is an established treatment of patients with ACS. PCI using trans-femoral approach (TFA) was embraced initially, and was replaced by the trans-radial approach (TRA). Many randomized studies comparing trans-radial and trans-femoral approaches in patients with coronary artery disease are available. Major scientific societies recommend trans-radial procedures in patients with ACS [2,3]. In contrast to prior studies, a recently published study showed no difference in outcomes according to the access (4). None of the included randomized studies were powered for all-cause mortality events. Hence, we aimed to do an updated systematic review and metanalysis to understand the safety and efficacy of TRA Vs TFA in patients with the ACS undergoing PCI.

Search strategy
We searched PubMed and Embase for all studies on patients with ACS [unstable angina, non-ST elevation myocardial infarction (NSTEMI) and STE myocardial infarction (ST elevation MI)] undergoing PCI (Since inception to April 2021) published in the English language. Also, we looked for cross-references in the screened studies, review articles, and prior similar metaanalysis along with conference proceedings to identify studies that can be potentially included. Our complete search strategy is described in the S1 File.

Study registration and ethical clearance
Our study protocol is registered with PROSPERO, International prospective register of systematic reviews (CRD42020185367). As it is a meta-analysis of already published studies whose data is available online, Institute ethical committee clearance was not obtained.

Study eligibility
Only randomized studies on patients with ACS or STEMI undergoing PCI comparing TRA with TFA in the English literature were eligible.

Eligibility assessment, data extraction, and validity assessment
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was followed in the execution of this systematic review and meta-analysis. Studies identified through the databases were incorporated into a single database file using Rayyan. Screening of the studies was performed using the title and abstracts after eliminating the duplicates by two independent authors (PR and PS). The full text of the screened articles was methodically assessed later for their eligibility for inclusion into the final data extraction and qualitative data synthesis. Validity assessment for individual studies was performed by two independent authors (PR&PS) using Risk of bias assessment was done using the Cochrane risk-of-bias tool for randomized trials version 2 (RoB 2). We obtained baseline characteristics of patients, procedural details, and clinical outcomes from the included studies. Data were extracted individually by two independent physicians (PR and PS). Any disagreement between the authors in the process of title and abstract screening, full-text screening, data extraction, and validity assessment was resolved by a third author (NS).

Outcomes
The primary outcome of our study was all-cause mortality at 30 days. The secondary outcomes included in-hospital mortality, major adverse cardio-vascular events (MACE) (composite of death, MI, or stroke) as defined by the study, net adverse clinical event (NACE) (composite of death, MI, stroke, or major bleeding), non-fatal myocardial infarction, non-fatal stroke, stent thrombosis, study-defined major bleeding, and minor bleeding, vascular complication, hematoma, pseudoaneurysm, access site bleeding, non-access site bleeding, need for transfusion, access site cross-over, contrast volume, procedure duration, study defined acute kidney injury, mean difference in creatinine, and hospital stay duration. When an outcome is reported only by a single study, it was not included in the final analysis.

Statistical analysis
Data extracted from the studies were noted into a Microsoft Excel sheet which was later imported into Review Manager Version 5.3 (The Nordic Cochrane Center, The Cochrane Collaboration Copenhagen, Denmark) and R version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria) for analysis. Random effect model was used in our meta-analysis. We executed a random effects meta-analysis using the Mantel-Haenszel method of pooling risk ratios (RR) with 95% confidence interval (CI) for all outcomes. We computed between-study heterogeneity by using the Higgins I 2 statistic. We defined low and high heterogeneity as I 2 <25% and >75% respectively. Publication bias for the primary outcome was assessed visually by the asymmetry in funnel plots. We performed a sensitivity analysis using fixed effect model. We intended to do subgroup analysis based on age (age<60/>60), sex, concurrent anticoagulation status, chronic kidney diseases (eGFR<60), Anemia (Hb<9/>9), and diabetes mellitus whenever the data of the same is available in more than two studies. We performed a leave-one-out sensitivity analysis to remove the effect of one study at a time on our results. We also did an analysis restricting to high-quality studies, and studies that included patients with STEMI alone. We calculated the anticipated power of the meta-analysis for major outcomes using information from previous literature and compared them with actual power attained at a 5% significance level. Several candidate covariates (mean age, % of females, % with diabetes, % with hypertension, % of smokers, and % of patients receiving GpIIb/IIIa inhibitors) were examined for association with treatment effect for all-cause mortality in ACS and STEMI patients, separately. A mixed-effects DerSimonian-Laird meta-regression was performed (based on predetermined criteria) to determine factors that significantly affected the treatment effect. Significant covariates were visualized using a bubble plot plotting treatment effect across categories of the covariate. A p-value of <0.05 was considered to be statistically significant. All Analyses were performed utilizing Review Manager version 5.3 (The Nordic Cochrane Center, The Cochrane Collaboration Copenhagen, Denmark) and R version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria).

Results
Our search strategy resulted in 1,339 studies. After exclusion of duplicates, and inclusion of articles from references, we ended up screening 702 studies for screening. After excluding 645 which were not fulfilling the inclusion criteria, we included 57 articles for full-text screening. We excluded 37 articles due to various reasons as elucidated (Fig 1 & S1 Table in S1 File) that resulted in 20 manuscripts for final quantitative data synthesis with two of those being subgroup analysis published separately.

Characteristics of included studies including risk-of bias assessment
We included 18 studies for our final analyses [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. Nine of them are single-center studies. Twelve of them were exclusively done in patients with STEMI. Though Jolly et al [13] and Valgimigli et al [19] have conducted their study in patients with ACS, they have reported their outcomes in patients with STEMI separately leading to a total of 14 studies with clinical outcomes for patients with STEMI. Risk of-bias for the primary outcome as assessed by RoB-2 showed a low risk for 5 studies, some concerns for 9 studies, and a high risk for 4 studies (S2 Table in S1 File).
We studied 21,296 patients from 18 studies in our systematic review with 10,616patients in the trans-radial arm and 10,680 patients in the trans-femoral arm. Baseline characteristics of the patient population in the included studies are shown in Table 1. Four of the included studies were having a large patient population (>500 patients) which contributed to the majority of the patient population in our meta-analysis [4,5,17,19]. Trials differed in the use of anticoagulation with unfractionated heparin, low molecular weight heparin and bivalirudin, and usage of vascular-closure devices ( Table 1).

Clinical outcomes
The primary outcome of the study being 30-day mortality in patients with ACS was available in 10 studies only. Out of 20,122 patients with 10,037 patients in the trans-radial arm and 10,085 patients in the trans-femoral arm, we observed 30-day mortality in 174 and 232 patients, respectively underscoring the mortality benefit with the trans-radial approach [(1.7% vs. 2.3%; RR: 0.75; 95% CI: 0.62-0.91; P = 0.004; I 2 = 0%); Fig 2a]. A funnel plot observation showed no publication bias (S1 Fig in S1 File). A sensitivity analysis using a fixed-effect model revealed the same results (S3 Table in S1 File). A leave-one study at a time analysis showed a similar result favoring trans-radial procedure. When we restricted our analysis to high-quality RCTs with low-risk bias, we found similar results [(1.7% vs.2.2%; RR: 0.76; 95% CI: 0.62-0.93; P = 0.007; I 2 = 0%) Fig 2b]. There was no significant difference in the primary outcome when subgroup analysis was done based on the use of bivalirudin as the predominant anticoagulant. (S2 Fig in S1 File) Similarly, subgroup analysis based on clinical presentation i, e., NSTEMI Vs STEMI showed no effect on the primary outcome (S3 Fig in S1 File).
We performed a separate analysis for studies with clinical outcomes for patients with STEMI. Out of 14 studies with a patient population of 11,027, only 9 studies with a total population of 10,465 patients reported 30-day mortality. We observed 120 events in the trans-radial arm and 172 events in the trans-femoral arm that resulted in a significant mortality benefit with trans-radial procedures as compared with trans-femoral procedures in patients with STEMI [(2.3% vs. 3.3%; RR: 0.71; 95% CI: 0.56-0.90; P = 0.004; I 2 = 0%) Fig 3a]. When we restricted our analysis to studies with low-risk bias, we found a similar result with reduced 30-day mortality in trans-radial arm [(2.2% vs. 3.1%; RR: 0.70; 95% CI: 0.50-0.99; P = 0.04; I 2 = 43%); Fig 3b].
In patients with ACS, we found reduced MACE with trans-radial procedures [(5.

Power of the meta-analysis for various outcomes and meta-regression
For the primary outcome, all-cause mortality at 30 days in patients with ACS, both anticipated and actual power was very high (>90%) regardless of the quality of studies (S8A-S8D Fig in S1    For ACS, the subgroup analysis did not reveal any significant covariates. Meta-regression carried out with mean age, % of females, % with diabetes, and % receiving GpIIb/IIIa inhibitors also did not reveal any significant covariates (S4 Table in S1 File) in patients with ACS. For patients with STEMI, % of patients receiving GpIIb/IIIa inhibitors was significantly associated with treatment effect in both subgroup and meta-regression analyses. In trials where �25% of patients received GpIIb/IIIa inhibitors, all-cause mortality was 46% lower in the TR group but in trials where <25% received the inhibitors, there was no difference between the TRA and TFA groups (S5 Table and

Discussion
The main findings of our meta-analysis that included only randomized controlled trials involving patients with acute coronary syndrome are (i) trans-radial procedures were associated with decreased all-cause mortality in patients with ACS undergoing PCI (ii) they are associated with decreased MACE, NACE, study-defined major bleeding, BARC class 3-5 bleeding, vascular complications, hematoma, and pseudoaneurysms without any difference in the in-hospital mortality rate, reinfarction, stroke, MACE, stent thrombosis, and severe bleeding requiring blood transfusions. We also found a significantly reduced 30-day mortality with trans-radial procedures in patients with STEMI alone. Such potential benefits of TRA may be due to reduced bleeding, early ambulation reducing infections and venous thromboembolisms. Our meta-analysis is holistic with separate analysis for the outcomes in patients with ACS and STEMI. We also analyzed the results based on the quality of studies in addition to the calculation for the power of the meta-analysis for clinically important outcomes along with meta-regression of various factors for those outcomes.
None of the included randomized studies were powered for all-cause mortality events. Hence, it is essential to do the metanalysis to know the effect of trans-radial procedures on outcomes. Though a large number of metanalysis is available comparing TRA with TFA, only a few of them are good quality metanalysis conducted in patients with ACS. The metanalysis performed by Ando et al [22] involving only high-quality studies with low risk of bias found reduced mortality, MACE, major bleeding in the trans-radial arm, similar to our results. Though the metanalysis by Ruiz-Rodriguez et al [23] was diluted by the amalgamation of data from RCTs and cohort studies, their result was similar to our results. However, the beneficial effects of trans-radial procedures were questioned by Le May et al who found no difference in 30 days all-cause mortality and MACE between trans-radial and transfemoral arms [4]. It was prematurely stopped, and event rates were lower than expected, resulting in a study underpowered to show any difference between the two arms in terms of mortality. It also needs to be emphasized that the above study used bivalirudin in most of the patients (Table 1), and vascular closure devices were used in more than 2/3 rd of the patients in the transfemoral arm. A closer look also showed a significantly reduced use of GpIIb/IIIa inhibitors (only 6%) which is usually low as compared with other studies (Table 1) and real-world practice [24]. We included the above trial in our metanalysis. Despite adding that trial in our meta-analysis, the result did not change. This underscores the beneficial effect of trans-radial PCI in patients with ACS. Ando et al found reduced occurrence of AKI in the TRA as compared with TFA, and found that such a reduced AKI event was predominantly responsible for the reduction in the all-cause mortality [25,26]. In contrast, in our metanalysis, we did not observe the same. Its needs to be emphasized that the above study was 2x2 factorial one. The sub-group analysis found that such a difference in acute kidney injury was observed in the heparin arm alone without any difference in the bivalirudin arm. This is a hypothesis generating finding as no difference between the arms was observed for the co-primary efficacy and safety end points in the MATRIX-Access or anti-thrombin program [19]. Whether the difference attributed could be because of heparin or bivalirudin needs to further studied in another RCT. Also, when studies were categorized based on �25% of patients receiving GpIIb/IIIa inhibitors, no significant difference in adverse clinical outcomes was observed between TRA and TFA groups. This underscores importance of bleeding (access and non-access site) related to them resulting in worse clinical outcomes.
Both MI and bleedings were associated with mortality [27]. Reduction in major bleeding has been shown to have a reduction in ischemic events. Bleeding, not only leads to interruption in anti-platelets, but also causes activation of inflammatory pathways that might lead to increased ischemic events. This is especially important in patients with STEMI where more potent anti-thrombotic would be used. Similar to our metanalysis, Jhand et al [28] have shown that TRA procedures are associated with lower all-cause mortality and bleeding in patients with STEMI. In systems of care where pharmaco-invasive and rescue PCI therapy is utilized for STEMI, TRA acts as a boon to prevent access site-related bleeding complications. Any access site-related bleeding in such a clinical situation that warrants interference in anti-platelet therapy will increase complications. Other possible benefits of TRA include early ambulation that will reduce hospital-related infections and venous-thromboembolism. Though we noticed increased procedural time with TRA, we did not find any difference in the arrival at PCI to the FBI which was in contrast to an analysis of the National Cardiovascular Disease Registry (NCDR) which revealed a modestly increased door-to-balloon time with TRA compared with TFA [29].
Vascular closure devices (VCDs) are increasingly used in interventional cardiology practice. VCDs may decrease the time to ambulation after the procedure. However, several studies including a recent metanalysis have shown that VCDs are not superior to manual compression in safety and efficacy [30,31]. Also, a recent meta-analysis showed the superiority of the transradial procedure over trans-femoral procedures where VCDs were used [32]. Hence, we believe trans-radial procedures should be considered superior to VCD-assisted TFA procedures unless proved otherwise by a sufficiently powered RCT. All the studies included in our meta-analysis have excluded patients with cardiogenic shock (CS). However, Gandhi et al [33] and Pancholy et al [34] showed that the trans-radial procedures reduced 30day mortality and MACE in patients with CS. Though it was based on observational studies, it could be extrapolated in patients with ACS and CS provided excellent operator experience is available. With the increase in the expertise of the operator and the institution, the ease of doing radial procedures will increase. Adopting a large volume radial procedural program even in patients with STEMI will lead to increasingly available expertise in patients with STEMI and CS that may improve patient outcomes.

Limitations
First, our study is a study-level meta-analysis of randomized studies and the search strategy was restricted to only articles published in English language and only Pubmed and Embase databases were screened for our meta-analysis. Second, many salient outcomes are not studied by all the available studies (For e.g., BARC 3-5 bleeding was reported only in the MATRIX and SAFARI-STEMI trials), and the definition used for some of the outcomes like myocardial infarction and major bleeding differs between the included studies. Third, several of the studies included in the final analysis except five of them as described above had a high-risk of bias or had some-concerns. However, a sub-group analysis restricted to studies with a low risk of bias showed similar results. Fourth, the anti-coagulant used in these trials were not the same (Table 1). However, Valgimigli et al have shown that there was no difference in MACE between bivalirudin and heparin arms [19]. Fifth, variation in the use of GpIIb/IIIa inhibitors, second anti-platelet agent and VCDs were also noticed among the included studies. Sixth, outcomes of radial procedures depend on expertise which was not pre-defined in most of the trials. In spite having many limitations, our metanalysis is the first powered metanalysis that answers the effect of TRA on all-cause mortality. We have described the results separately for patients with ACS and STEMI. In addition, we also analyzed the results based on the quality of studies which is very important to understand the quality of the results. Meta-regression for various factors like mean age, % of females, % with diabetes, and % receiving GpIIb/IIIa inhibitor were also used. Lastly, a properly done ultrasound-guided femoral access with less usage of GpIIb/IIIa inhibitors versus radial access has not been randomly studied. Until then, we may not generalize the results.

Conclusion
Our metanalysis conclude that in patients with ACS undergoing PCI, trans-radial approach is associated with reduced 30-day all-cause mortality (more so in patients with STEMI), MACE, NACE, study-defined major bleeding, BARC class 3-5 bleeding, vascular complications, hematoma, and pseudo-aneurysms. Hence, TRA should be considered as a default procedural access strategy in most of the patients with ACS undergoing PCI. All interventionists should strive hard to master TRA so as to improve patient outcomes.